Pain is perceived as a result of communication between the two main divisions—central and peripheral—of the nervous system. While the two divisions work together to produce our subjective experience, the central and peripheral nervous systems are anatomically and functionally different.
A painful stimulus impinging on a specialized pain receptor is propagated along a peripheral branch of a sensory axon to a neuron lying within a dorsal root ganglion (part of the peripheral nervous system) and then along a central branch of the axon into the spinal cord (central nervous system). The signal is subsequently relayed to a central nervous system neuron in the spinal cord which in turn passes the signal, through its axon, to the opposite (“contralateral”) side of the spinal cord and then up to pain perceiving structures in the brain.
Peripheral pain receptors are located on free nerve endings which can respond to mechanical, thermal or chemical stimuli. Pain can be acute or chronic. Acute pain is typically transmitted from the receptor through Aδ sensory nerve fibers, which are thinly coated with the insulating compound, myelin, which facilitates impulse conduction. Chronic pain typically travels through C fibers, which, because they are unmyelinated, transmit impulses slowly, leading to the characteristic dull, diffuse nature of chronic pain. Chemical mediators of inflammation such as bradykinin and prostaglandins stimulate pain receptors, and are important agents in chronic pain syndromes, such as the persistent pain associated with arthritis or nerve inflammation.
The perception of pain can be altered at various stages of the pain pathway. For example, the painful stimulus can be eliminated by administering a local anesthetic to the peripheral receptor. Drugs like opioids were classically known to intervene at the central nervous system stage of the pain pathway, and non-steroidal anti-inflammatory drugs at the peripheral stage (although it is now realized that there is some cross-reactivity of both). Likewise, what is perceived as chronic pain (not due to primary spinal cord injury) is typically associated with sensitization of peripheral pain receptors as well as changes in the excitability of spinal neurons, and therefore has both peripheral and central nervous system components. The peripheral and central components involved in chronic pain are referred to, respectively, as “primary” and “secondary” hyperalgesia (Urban and Gebhart, 1999, citing Woolf, 1983 and La Motte et al., 1991).
In terms of the central nervous system components of chronic pain, the spinal cord neuron which receives the stimulus from the dorsal root ganglion axon, exhibits changes in gene expression in the context of chronic pain and is believed to contribute to the phenomenon of “central sensitization” or “spinal hyperalgesia.” Spinal N-methyl-D-aspartate (“NMDA”) receptors are believed to play an important role in this process (Urban and Gebhart, 1999, citing Urban and Gebhart, 1998; Palacek et al., 2003; Lee et al., 1993). Spinal cord injury without activation of the peripheral nervous system can also produce spinal hyperalgesia resulting in a central pain syndrome (Zhang et al., 2005). Central neuropathic pain has been associated with phosphorylation of the transcription factor, cyclic AMP response element binding protein (“CREB”) (Cron et al., 2005).
Regarding the peripheral nervous system component of chronic pain associated with nerve injury (“neuropathic pain”), persistent neuropathic pain is a major clinical problem that has mostly resisted effective treatment. In humans (Gracely et al., 1992) and mammalian model systems (Millan, 1999), persistent pain after nerve injury is associated with long-term hyperexcitability (LTH) of sensory neurons (SNs) having axons in the injured nerve. LTH is manifested as increased sensitivity to electrical stimuli in the SN cell body and axon at the injury site (Wall and Devor, 1983; Study and Kral, 1996; Zhang et al., 1997; Chen and Devor, 1998; Kim et al., 1998; Abdulla and Smith, 2001). These changes result in discharge of action potentials from SNs at rest or during innocuous stimulation, leading to continuing excitation of higher order neurons in the central nervous system and to secondary, or spinal hyperalgesia and persistent pain. Because the appearance of LTH involves alterations in gene expression (Waxman et al., 1994; Wang et al., 2002; Park et al., 2003), a central question is, how are such changes in the nucleus induced by an injury that occurs far from the cell body? Answering this question has been extremely difficult using the complex mammalian nervous system.
An experimentally favorable alternative is the homogeneous cluster of SNs that reside in the bilateral pleural ganglia of the mollusk Aplysia californica (Walters et al., 2004). Noxious mechanical stimulation of the body wall (Walters et al., 1983a) or crushing SN axons in vivo or in vitro, elicits an LTH with electrophysiological properties similar to those seen after axotomy of mammalian SNs (Walters et al., 1991; Walters, 1994; Ambron et al., 1996; Bedi et al., 1998; Ungless et al., 2002; Sung and Ambron, 2004). The LTH appears after a delay, suggesting that its induction after nerve crush is attributable to a positive molecular injury signal (Walters et al., 1991; Ambron and Walters, 1996; Lin et al., 2003). Two studies support this idea. First, blocking axonal transport after nerve injury in excised nervous systems prevented the appearance of LTH (Gunstream et al., 1995). Second, LTH was induced in noninjured SNs by injecting axoplasm from injured axons (Ambron et al., 1995). LTH was also elicited in the SNs after intrasomatic injection of an ERK (extracellular signal-regulated kinase) member of the MAPK (mitogen-activated protein kinase) family (Sung et al., 2000). Other experiments have suggested that cGMP and PKG (cGMP-dependent protein kinase; protein kinase G) are probably involved (Lewin and Walters, 1999). However, despite these observations, the identity of the signal from the axon, how PKG and the ERK are activated, or how these kinases might interact were not known. Moreover, LTH was also reported to be induced by cAMP acting on PKA (protein kinase A) in a learning paradigm (Dale et al., 1988; Scholz and Byrne, 1988).
U.S. Pat. No. 6,476,007 by Tao and Johns (“Tao and Johns”) relates to a proposed signalling pathway in the central nervous system in which stimulation of an N-methyl-D-aspartate (“NMDA”) receptor leads to activation of nitric oxide synthase (“NOS”) and production of nitric oxide (“NO”), which then stimulates guanylate cylase (“GC”) and the production of cyclic guanoside monophosphate (cGMP), which in turn activates cGMP-dependent protein kinase 1α (“PKG”). It was observed that administration of the PKG inhibitor Rp-8-[4-chlorophenyl)thio-cGMPS triethylamine into the central nervous system by intrathecal administration, after the induction of an inflammatory response, produced significant antinociception in rats 10 and 60 minutes later. Further, they noted an upregulation of PKG expression in the lumbar spinal cord 96 hours after noxious stimulation was blocked by administration of a neuronal NOS inhibitor, a soluble GC inhibitor, and a NMDA receptor antagonist.
However, while Tao and Johns purports to address the mechanism of inflammatory hyperalgesia in the central nervous system, prior to the present invention the need remained to determine the mechanism of pain, and in particular chronic pain and long-term hyperexcitability, in the sensory neurons of the peripheral nervous system.
The need to address the mechanism of pain in the peripheral nervous system is important for several reasons, the first of which is drug accessibility. The central nervous system is sequestered from the rest of the body by the blood-brain-barrier, which is created by tight junctions between endothelial cells of the central nervous system and prevents many therapeutic drugs from ever reaching the central nervous system. Because of the extremely limited permeability of the blood-brain-barrier, treatment of spinal hyperalgesia according to Tao and Johns would be problematic. The ability, according to the present invention, to treat the primary hyperalgesia aspect of pain by delivering agents to the peripheral nervous system, which does not have the same permeability issues, confers a substantial advantage.
A second reason that treatment of peripheral pain mechanisms is important is that the periphery is the portal for pain perception. The present invention offers the advantage of intervening in subjective pain as it first arises, such as in the context of a normally non-painful stimulous which results in the perception of pain as a result of long term hyperexcitability (LTH). Subjective pain can be triggered in chronic pain sufferers by stimuli—such as the light touch of a sheet or a passing breeze—which would not normally be painful. The present invention is directed at this first stage of the pain pathway.